{"gene":"IMPDH2","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2020,"finding":"Cryo-EM structures of human IMPDH2 in active and inactive conformations revealed that filament assembly tunes allosteric regulation by making the enzyme less sensitive to GTP-mediated feedback inhibition, explaining why self-assembly occurs under conditions of high guanine nucleotide demand.","method":"Cryo-EM structural determination of multiple IMPDH2 conformations (active and inactive) with functional validation of allosteric regulation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures with multiple conformational states and functional mechanistic interpretation","pmids":["31999252"],"is_preprint":false},{"year":2017,"finding":"IMPDH2 was identified as an intracellular target of the CyclophilinA (PPIA)–Sanglifehrin A (SFA) binary complex; the resulting ternary complex does not inhibit IMPDH2 enzymatic activity but instead interacts with the CBS (cystathionine-β-synthase) domain of IMPDH2 to modulate cell growth, demonstrating isoform selectivity for IMPDH2 over IMPDH1.","method":"Affinity pulldown, Co-IP, enzymatic activity assays, isoform selectivity assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal pulldown with enzymatic and cellular functional validation, multiple orthogonal methods","pmids":["28076787"],"is_preprint":false},{"year":2019,"finding":"ANKRD9 facilitates ubiquitin-mediated degradation of IMPDH2 under basal conditions; upon nutrient limitation ANKRD9 co-assembles with IMPDH2 into rod-like filaments in which IMPDH2 is stable. The conserved Cys109–Cys110 motif in ANKRD9 is required for the vesicle-to-rod transition and for binding/regulation of IMPDH2. Guanosine acts as a metabolic switch reversing ANKRD9/IMPDH2 rod assembly.","method":"Co-immunoprecipitation, site-directed mutagenesis of ANKRD9, fluorescence microscopy, IMPDH2 knockdown/overexpression, guanosine rescue experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, mutagenesis, live imaging, KD/KO with rescue), single lab but strong mechanistic depth","pmids":["31337707"],"is_preprint":false},{"year":2023,"finding":"Disease-associated point mutations in IMPDH2 linked to dystonia and neurodevelopmental disorders disrupt GTP-mediated allosteric regulation; cryo-EM structures of one mutant show a shift in conformational equilibrium toward a more active (GTP-inhibition-resistant) state.","method":"Cryo-EM structural analysis of IMPDH2 mutants, enzymatic activity assays measuring GTP inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures plus functional enzymatic assays with disease variants","pmids":["37414152"],"is_preprint":false},{"year":2024,"finding":"IMPDH2 serine 122 is phosphorylated by CDK1, which attenuates IMPDH2 catalytic activity for IMP oxidation and represses allosteric modulation by purine nucleotides. FGFR signaling triggers dephosphorylation of Ser122 via PP2A (assembled through FGFR3-mediated phosphorylation of PPP2R1A-Tyr261, enabling PPP2CA–PPP2R1A–IMPDH2 interactions), thereby activating IMPDH2 to support guanine nucleotide synthesis, S-phase completion, and cell proliferation.","method":"In vitro kinase assay (CDK1), site-directed mutagenesis, phosphoproteomics, Co-IP, enzymatic activity assays, cell cycle analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro kinase assay plus mutagenesis, Co-IP of PP2A complex, multiple functional readouts","pmids":["39739531"],"is_preprint":false},{"year":2024,"finding":"Nuclear IMPDH2 interacts with PARP1 on chromatin and modulates PARP1 activity by controlling local NAD+ availability; IMPDH2 chromatin localization is DNA damage-dependent, and IMPDH2 repression leads to DNA damage accumulation. Restricting IMPDH2 exclusively to the nucleus depletes nuclear NAD+, triggering PARP1 cleavage and cell death.","method":"Chromatin fractionation, Co-IP on chromatin, NAD+ measurements, IMPDH2 knockdown with DNA damage readouts, nuclear-restricted IMPDH2 overexpression","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (fractionation, Co-IP, NAD+ quantification, KD/forced localization) with strong functional link","pmids":["39532854"],"is_preprint":false},{"year":2025,"finding":"USP5 deubiquitinase binds IMPDH2 via its N-terminal cryptic ZnF-UBP and ZnF-UBP domains (interacting with IMPDH2 residues 251–514), removes Lys48-linked ubiquitin chains from IMPDH2, and thereby prevents its proteasomal degradation and stabilizes IMPDH2 protein levels to promote hepatocellular carcinoma proliferation and EMT.","method":"Co-IP domain mapping, deubiquitination assay (Lys48-linkage-specific), shRNA knockdown, xenograft models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 — deubiquitination biochemical assay with linkage specificity, domain mapping, and in vivo rescue","pmids":["40164869"],"is_preprint":false},{"year":2024,"finding":"JOSD2 deubiquitinase binds the C-terminus of IMPDH2 and cleaves K63-linked polyubiquitin chains at IMPDH2-K134, suppressing IMPDH2 enzymatic activity and preventing downstream NF-κB activation and inflammation in macrophages.","method":"Co-IP, site-specific deubiquitination assay (K63-linkage), JOSD2 knockout mice, myeloid-specific deletion with bone marrow transplantation","journal":"Acta pharmaceutica Sinica. B","confidence":"High","confidence_rationale":"Tier 1–2 — linkage-specific deubiquitination assay, K134 site identification, in vivo genetic models","pmids":["40177575"],"is_preprint":false},{"year":2015,"finding":"Conditional deletion of Impdh2 in early neural crest cells (using Wnt1-Cre) in mice produces defects in multiple neural crest derivatives, including intestinal aganglionosis, craniofacial skeletal agenesis, and cardiac outflow tract malformations, demonstrating that IMPDH2-mediated guanine nucleotide synthesis is essential for neural crest cell proliferation and development.","method":"Conditional knockout mouse (Wnt1-Cre × Impdh2flox), Rosa26 reporter lineage tracing, histological analysis of neural crest derivatives","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with multiple specific phenotypic readouts in defined cell lineage","pmids":["26546974"],"is_preprint":false},{"year":2015,"finding":"IMPDH2 is a major structural component (building block) of cytoplasmic rod/ring (RR) structures; microinjection of affinity-purified anti-IMPDH2 antibodies into live cells caused disassembly of RR structures within 10 minutes, demonstrating that IMPDH2 is essential for RR integrity and that mature RR are primarily stationary structures.","method":"Microinjection of anti-IMPDH2 antibodies into live cells, GFP-tagged IMPDH2 live imaging, fluorescence microscopy","journal":"Cell & bioscience","confidence":"High","confidence_rationale":"Tier 2 — direct live-cell antibody perturbation experiment with two independent methods (antibody injection + GFP-IMPDH2 imaging)","pmids":["25601894"],"is_preprint":false},{"year":2015,"finding":"Assembly of IMPDH2-based rod/ring (RR) structures in cells is induced by inhibition of GTP biosynthesis (by ribavirin or mycophenolic acid) and is cell-type dependent; CTPS and IMPDH2 can form mixed or separate RR structures depending on cell type and the inhibitor used, indicating that IMPDH2 and CTPS independently organize into cytoophidia.","method":"Drug treatment (DON, ribavirin, MPA), immunofluorescence, transfection of NHA-tagged CTPS1 in HeLa and COS-7 cells","journal":"Journal of genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, direct imaging with pharmacological manipulation but no biochemical reconstitution","pmids":["26165495"],"is_preprint":false},{"year":2022,"finding":"SARS-CoV-2 Nsp14 protein physically interacts with IMPDH2, and this interaction is required for Nsp14-mediated NF-κB activation and pro-inflammatory cytokine (IL-6, IL-8) induction; IMPDH2 knockdown or pharmacological inhibition (ribavirin, mycophenolic acid) abolishes Nsp14-driven NF-κB activation and restricts SARS-CoV-2 replication.","method":"Co-IP confirmation of Nsp14–IMPDH2 interaction, siRNA knockdown, pharmacological inhibition, NF-κB reporter assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP confirmed interaction with functional KD and pharmacological validation, single lab","pmids":["36177032"],"is_preprint":false},{"year":2020,"finding":"FANCI directly binds IMPDH2 (shown by Co-IP), decreases IMPDH2 degradation, and promotes MEK/ERK/MMP signaling activation; overexpression of IMPDH2 reverses the growth inhibitory effects of FANCI knockdown in lung adenocarcinoma cells.","method":"Co-immunoprecipitation, immunofluorescence microscopy, Western blotting, FANCI knockdown with IMPDH2 rescue","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP with epistasis rescue experiment","pmids":["32021289"],"is_preprint":false},{"year":2021,"finding":"CircPFKP directly interacts with IMPDH2 and promotes guanine nucleotide biosynthesis; replenishment of the intracellular guanine nucleotide pool reverses the proliferation-inhibitory effects of circPFKP knockdown, placing IMPDH2 downstream of circPFKP in prostate cancer cell proliferation.","method":"RNA-protein interaction assays, circRNA knockdown, guanosine rescue experiments, cell cycle analysis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, direct RNA-protein interaction with metabolite rescue supporting pathway placement","pmids":["34673127"],"is_preprint":false},{"year":2024,"finding":"IMPDH2 cytoophidium (filament) formation in neurodegeneration-resistant brain regions protects against GTP deprivation in AMPD2-deficient mice; IMPDH2 filaments are abundant in resistant regions but sparse in the vulnerable hippocampal dentate gyrus, and blocking IMPDH2 polymerization impairs GTP levels and growth of AMPD2-deficient neural progenitor cells.","method":"Mouse knockout models, immunofluorescence of IMPDH2 filaments, dominant-negative IMPDH2 variant to block polymerization, neural progenitor cell growth assays","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo mouse model with mechanistic IMPDH2 filament perturbation and cell growth readout","pmids":["39075237"],"is_preprint":false},{"year":2024,"finding":"IMPDH2 filaments resist allosteric inhibition by GTP in regenerating Xenopus tropicalis tadpole tail tissue; IMPDH2 inhibition impairs tail regeneration and reduces cell proliferation, demonstrating that IMPDH2 filament assembly is a physiologically relevant regulatory mechanism in vertebrate tissue regeneration.","method":"Chemical inhibition of IMPDH2, IMPDH2-fluorescent fusion live imaging in regenerating tadpole tail, cell proliferation assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — direct in vivo imaging of endogenous IMPDH2 filaments with functional inhibition in vertebrate regeneration context","pmids":["39131357"],"is_preprint":true},{"year":2025,"finding":"An IMPDH2 neurodevelopmental disorder mutant (S160del) disrupts filament assembly by destabilizing dimerization of regulatory Bateman domains (shown by cryo-EM), alters purine pools in vivo in Xenopus tropicalis, and disrupts somite organization; GTP inhibition insensitivity of S160del is separable from Bateman domain dimerization, indicating that filament assembly and allosteric GTP regulation are mechanistically distinct.","method":"Cryo-EM structural analysis of S160del mutant, Xenopus tropicalis in vivo expression, metabolomics of purine pools, developmental phenotyping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure of disease mutant combined with in vivo metabolomics and developmental phenotypes in vertebrate model","pmids":["41343675"],"is_preprint":false},{"year":2009,"finding":"A promoter SNP in IMPDH2 (c.-95T>G) disrupts a cyclic AMP response element (CRE) binding site and significantly decreases IMPDH2 transcriptional activity (~55–65% reduction) as measured by luciferase reporter assays in transfected HEK293 and Jurkat cells.","method":"Luciferase reporter gene assay, transient transfection in two cell lines","journal":"Genetic testing and molecular biomarkers","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional reporter assay with two cell types, but single lab","pmids":["19810816"],"is_preprint":false},{"year":2010,"finding":"An IMPDH2 allozyme (Phe263) shows decreased enzymatic activity primarily due to accelerated protein degradation; these functional consequences are supported by the IMPDH2 X-ray crystal structure context.","method":"Enzyme activity assays, protein stability assays, resequencing of IMPDH2 in 288 individuals, X-ray crystal structure interpretation","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — direct enzymatic and protein stability assays on variant allozyme","pmids":["20718729"],"is_preprint":false},{"year":2024,"finding":"Impdh2 deletion in myeloid lineage cells (Impdh2LysM-/- mice) impairs osteoclastogenesis by suppressing osteoclast marker gene expression and mitochondrial oxidative phosphorylation, and alleviates ovariectomy-induced bone loss in vivo. IMPDH inhibitor (MPA) treatment induces IMPDH2 cytoophidium (filament) formation coincident with osteoclast differentiation block.","method":"Conditional myeloid-specific Impdh2 knockout mouse, histomorphometry, qPCR, genome-wide transcriptomics, MPA pharmacological inhibition, OVX mouse model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — clean conditional KO with specific cellular and transcriptomic phenotypes, replicated with pharmacological inhibition","pmids":["38959733"],"is_preprint":false},{"year":2023,"finding":"EBV induces IMPDH2 expression through EBNA2-dependent and MYC-dependent mechanisms (established using EBNA2 and LMP1 knockout viruses), leading to nucleolar hypertrophy and efficient B-cell growth transformation; IMPDH2 inhibition with MPA blocks this transformation.","method":"EBV knockout virus infections (EBNA2 KO, LMP1 KO), RNA-seq, MPA pharmacological inhibition, xenograft mouse model","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 2 — viral genetic dissection with KO viruses, RNA-seq, and in vivo model","pmids":["37409959"],"is_preprint":false},{"year":2024,"finding":"IMPDH2 interacts with c-Myc to protect it from ubiquitination; the natural compound vitexicarpin binds IMPDH2, disrupts the IMPDH2–c-Myc interaction, and promotes c-Myc ubiquitination leading to EMT inhibition in colorectal cancer.","method":"Co-IP, ubiquitination assay, CETSA, label-free quantitative proteomics, Biacore binding assay, molecular docking, IMPDH2 overexpression/knockdown rescue","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple orthogonal binding and functional methods but single lab","pmids":["39008915"],"is_preprint":false},{"year":2025,"finding":"IMPDH2 is directly phosphorylated at tyrosine 233 (Y233) within its Bateman domain by ALK and SRC oncogenic kinases; Y233 phosphorylation is essential for IMPDH2 enzymatic activity. Phosphoinositide-3-phosphate (PI3P) selectively binds and inhibits IMPDH2 but not IMPDH1, representing an isoform-specific lipid-mediated regulatory mechanism.","method":"Peptide-based mutagenesis, in vitro kinase assays (ALK, SRC), enzymatic assays, PI3P binding assays, isoform selectivity comparison","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro kinase and enzymatic assays with mutagenesis, but preprint only","pmids":["bio_10.1101_2025.08.19.667179"],"is_preprint":true},{"year":2025,"finding":"IMPDH2 interacts with SRPK1 in CD4+ T cells (confirmed by mass spectrometry, Co-IP, and confocal colocalization); IMPDH2 upregulates SRPK1 expression, which in turn activates the AKT/mTOR signaling pathway to promote CD4+ T cell proliferation and suppress apoptosis.","method":"Mass spectrometry interaction screen, Co-IP, confocal fluorescence colocalization, IMPDH2 knockdown/overexpression, Western blot of AKT/mTOR pathway","journal":"Clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 — MS-confirmed interaction validated by Co-IP and colocalization, with functional pathway readout","pmids":["41213488"],"is_preprint":false},{"year":2026,"finding":"tRF-1432 (a 5'-tRNA^Val-CAC-derived fragment generated by angiogenin cleavage) directly interacts with RNA-binding protein RBMS1, attenuating RBMS1-mediated destabilization of IMPDH2 mRNA and thereby increasing IMPDH2 protein levels and GTP-dependent chemoresistance in breast cancer.","method":"High-throughput sequencing, RNA-protein interaction assays, RBMS1 knockdown/rescue, IMPDH2 mRNA stability assays, syngeneic tumor models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct RNA-protein interaction with mRNA stability mechanistic follow-up and in vivo model","pmids":["41791844"],"is_preprint":false},{"year":2023,"finding":"IMPDH2 forms localized spots at branching sites and distal ends of astrocyte stem processes in adult mouse hippocampus, suggesting a role in site-specific GTP synthesis and local small GTPase regulation at specialized nodes in astrocyte branches.","method":"Immunofluorescence of endogenous IMPDH2 in adult mouse hippocampus and primary astrocyte cultures, quantitative distribution analysis","journal":"Genes to cells","confidence":"Low","confidence_rationale":"Tier 3 — localization data without direct functional consequence demonstrated","pmids":["38009721"],"is_preprint":false},{"year":2021,"finding":"IMPDH2 cytoophidium forms in vivo in growing mouse oocytes and in granulosa cells following LH surge; MPA-induced IMPDH2 cytoophidium formation in cumulus cells coincides with meiosis resumption in oocytes mediated through the mTOR pathway, and this effect is reversed by guanosine supplementation, linking IMPDH2 filament formation to oocyte meiotic competence.","method":"In vivo immunofluorescence in mouse ovary, MPA pharmacological inhibition, mTOR pathway inhibitor, guanosine rescue, confocal microscopy","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — in vivo localization with pharmacological perturbation and metabolite rescue linking IMPDH2 filaments to meiotic signaling","pmids":["34124077"],"is_preprint":false}],"current_model":"IMPDH2 is the rate-limiting enzyme catalyzing the first committed step of de novo guanine nucleotide biosynthesis (IMP → XMP), whose activity is allosterically inhibited by GTP; it reversibly polymerizes into filaments that reduce sensitivity to GTP-mediated feedback inhibition, and its activity is regulated post-translationally by CDK1-mediated phosphorylation at Ser122 (inhibitory, reversed by FGFR-activated PP2A), by ALK/SRC-mediated phosphorylation at Tyr233 (activating), by USP5-mediated deubiquitination (stabilizing) and JOSD2-mediated K63-deubiquitination (inhibitory), and by ANKRD9-mediated ubiquitination-dependent degradation; in the nucleus IMPDH2 modulates PARP1 activity via NAD+ availability to fine-tune the DNA damage response, and gain-of-function disease mutations associated with dystonia and neurodevelopmental disorders disrupt GTP allostery by shifting the conformational equilibrium toward an active state and destabilizing Bateman domain dimerization required for filament assembly."},"narrative":{"teleology":[{"year":2009,"claim":"Establishing that IMPDH2 transcription is regulated by a cAMP response element answered how signaling pathways control enzyme abundance at the promoter level.","evidence":"Luciferase reporter assays with a promoter SNP (c.−95T>G) disrupting a CRE site in HEK293 and Jurkat cells","pmids":["19810816"],"confidence":"Medium","gaps":["Endogenous transcription factor binding not confirmed by ChIP","In vivo relevance of this SNP not tested"]},{"year":2010,"claim":"Demonstrating that a naturally occurring IMPDH2 allozyme (Phe263) loses activity primarily through accelerated degradation revealed that protein stability, not just catalytic efficiency, governs IMPDH2 function.","evidence":"Enzymatic activity and protein stability assays on variant allozyme, interpreted against X-ray crystal structure","pmids":["20718729"],"confidence":"Medium","gaps":["Degradation pathway (ubiquitin vs. autophagy) not identified","Clinical pharmacogenomic impact not quantified in vivo"]},{"year":2015,"claim":"Establishing IMPDH2 as the essential structural building block of cytoplasmic rod/ring (cytoophidium) structures, and showing that these filaments form in response to GTP biosynthesis inhibition, defined a novel metabolic ultrastructure and its assembly triggers.","evidence":"Microinjection of anti-IMPDH2 antibodies causing rapid RR disassembly; pharmacological induction by ribavirin/MPA with immunofluorescence in multiple cell types","pmids":["25601894","26165495"],"confidence":"High","gaps":["Atomic-resolution filament architecture not yet determined at this time","Functional consequence of filament assembly on enzyme kinetics not resolved"]},{"year":2015,"claim":"Conditional deletion of Impdh2 in neural crest cells demonstrated that IMPDH2-dependent guanine nucleotide synthesis is essential for neural crest proliferation and organogenesis, establishing a non-redundant developmental role.","evidence":"Wnt1-Cre conditional knockout mouse with Rosa26 lineage tracing showing aganglionosis, craniofacial agenesis, and cardiac outflow tract defects","pmids":["26546974"],"confidence":"High","gaps":["Whether IMPDH1 can partially compensate in other lineages not tested","Mechanism downstream of GTP depletion (proliferation vs. differentiation defect) not dissected"]},{"year":2017,"claim":"Identification of IMPDH2 as the isoform-selective target of the CyclophilinA–Sanglifehrin A complex revealed a non-catalytic regulatory interface on the CBS/Bateman domain that modulates cell growth.","evidence":"Affinity pulldown and Co-IP with enzymatic activity assays showing no catalytic inhibition; isoform selectivity over IMPDH1","pmids":["28076787"],"confidence":"High","gaps":["Structural basis of PPIA–SFA–IMPDH2 ternary complex not resolved","Growth-modulating mechanism downstream of CBS domain engagement unknown"]},{"year":2019,"claim":"Discovery that ANKRD9 acts as a metabolic switch — promoting IMPDH2 ubiquitin-dependent degradation basally but co-assembling into stabilizing filaments under nutrient limitation — revealed how IMPDH2 protein levels are coupled to metabolic state.","evidence":"Co-IP, mutagenesis of ANKRD9 Cys109–Cys110, fluorescence microscopy of rod assembly, guanosine rescue experiments","pmids":["31337707"],"confidence":"High","gaps":["E3 ligase that ubiquitinates IMPDH2 via ANKRD9 not identified","Stoichiometry of ANKRD9 within filaments unknown"]},{"year":2020,"claim":"Cryo-EM structures of IMPDH2 filaments in active and inactive conformations answered the long-standing question of how polymerization is functionally meaningful: filament assembly desensitizes the enzyme to GTP feedback inhibition, explaining filament formation under high guanine nucleotide demand.","evidence":"Cryo-EM of multiple conformational states with allosteric regulation functional assays","pmids":["31999252"],"confidence":"High","gaps":["In vivo validation that filament-mediated desensitization drives proliferative advantage not yet shown","Dynamics of filament assembly/disassembly in real time not captured"]},{"year":2021,"claim":"Observation of IMPDH2 cytoophidium formation in mouse oocytes and granulosa cells in vivo, with pharmacological evidence linking filaments to mTOR-dependent meiosis resumption, extended the physiological relevance of IMPDH2 polymerization to reproductive biology.","evidence":"In vivo immunofluorescence in mouse ovary, MPA-induced filament formation with mTOR inhibitor and guanosine rescue","pmids":["34124077"],"confidence":"Medium","gaps":["Direct genetic test (IMPDH2 polymerization-deficient mutant) in oocytes not performed","Whether filaments alter local GTP pools in granulosa cells not measured"]},{"year":2022,"claim":"Demonstrating that SARS-CoV-2 Nsp14 physically engages IMPDH2 to activate NF-κB signaling uncovered a viral hijacking mechanism that links purine metabolism to innate immune activation.","evidence":"Co-IP of Nsp14–IMPDH2, siRNA knockdown and pharmacological inhibition abolishing NF-κB reporter activation","pmids":["36177032"],"confidence":"Medium","gaps":["Whether IMPDH2 enzymatic activity or a scaffolding role is required for Nsp14-mediated NF-κB not distinguished","Interaction validated in single lab only"]},{"year":2023,"claim":"Cryo-EM structures of disease-linked IMPDH2 mutants established the molecular basis of dystonia and neurodevelopmental disorders: mutations shift the conformational equilibrium toward an active, GTP-inhibition-resistant state.","evidence":"Cryo-EM of mutant IMPDH2, enzymatic assays measuring reduced GTP inhibition","pmids":["37414152"],"confidence":"High","gaps":["Neuronal cell-type-specific consequences of gain-of-function not modeled","Whether pharmacological IMPDH2 inhibition can rescue disease phenotype untested"]},{"year":2024,"claim":"Discovery that CDK1 phosphorylates IMPDH2 at Ser122 to inhibit activity, and that FGFR signaling reverses this through PP2A-mediated dephosphorylation, established a cell-cycle-coupled regulatory circuit linking mitogenic signaling to guanine nucleotide supply during S-phase.","evidence":"In vitro CDK1 kinase assay, phosphosite mutagenesis, Co-IP of PP2A complex, cell cycle analysis","pmids":["39739531"],"confidence":"High","gaps":["Whether Ser122 phosphorylation affects filament assembly not tested","In vivo validation in animal models lacking"]},{"year":2024,"claim":"Showing that nuclear IMPDH2 interacts with PARP1 on chromatin and controls local NAD+ availability revealed an unexpected non-canonical role: IMPDH2 couples purine metabolism to the DNA damage response by modulating PARP1 activity.","evidence":"Chromatin fractionation, Co-IP on chromatin, NAD+ measurements, nuclear-restricted IMPDH2 overexpression causing PARP1 cleavage and cell death","pmids":["39532854"],"confidence":"High","gaps":["Mechanism of IMPDH2 nuclear import not identified","Whether IMPDH2 catalytic activity or scaffolding is required on chromatin not fully separated"]},{"year":2024,"claim":"Demonstrating that IMPDH2 filaments accumulate in neurodegeneration-resistant brain regions of AMPD2-deficient mice, and that blocking polymerization impairs neural progenitor GTP levels, established filament formation as a neuroprotective mechanism against purine imbalance.","evidence":"Mouse knockout model of AMPD2, immunofluorescence of IMPDH2 filaments, dominant-negative polymerization mutant in neural progenitors","pmids":["39075237"],"confidence":"Medium","gaps":["Causal relationship between filament abundance and regional vulnerability not genetically proven","Whether therapeutic promotion of filament assembly is feasible not explored"]},{"year":2024,"claim":"Myeloid-specific Impdh2 deletion suppressed osteoclastogenesis and protected against ovariectomy-induced bone loss, revealing IMPDH2 as a metabolic gatekeeper of osteoclast differentiation through control of oxidative phosphorylation.","evidence":"LysM-Cre conditional knockout, histomorphometry, transcriptomics, MPA pharmacological inhibition in OVX mouse model","pmids":["38009733"],"confidence":"Medium","gaps":["Whether GTP depletion or secondary metabolic effects drive osteoclast block not dissected","Contribution of IMPDH1 in myeloid cells not assessed"]},{"year":2025,"claim":"Identification of USP5 as a K48-linkage-specific deubiquitinase stabilizing IMPDH2, and JOSD2 as a K63-linkage-specific deubiquitinase suppressing IMPDH2 activity at K134, revealed that distinct ubiquitin chain types exert opposing regulatory outcomes — stability versus activity modulation.","evidence":"USP5: domain mapping, K48-specific DUB assay, xenograft rescue; JOSD2: K63-specific DUB assay at K134, JOSD2 KO mice with macrophage phenotypes","pmids":["40164869","40177575"],"confidence":"High","gaps":["E3 ligases conjugating K48 and K63 chains on IMPDH2 not identified","Whether ubiquitin editing occurs on filament-assembled versus free IMPDH2 unknown"]},{"year":2025,"claim":"Cryo-EM of the S160del disease mutant demonstrated that filament assembly and allosteric GTP regulation are mechanistically separable: S160del destabilizes Bateman domain dimerization (disrupting filaments) while independently retaining GTP insensitivity, refining the structure-function model of IMPDH2 regulation.","evidence":"Cryo-EM of S160del, Xenopus in vivo expression with metabolomics and somite phenotyping","pmids":["41343675"],"confidence":"High","gaps":["Whether filament disruption alone is sufficient for disease pathogenesis not tested","Neuronal-specific consequences of Bateman domain destabilization not modeled in mammalian systems"]},{"year":null,"claim":"Key unresolved questions include the identity of E3 ubiquitin ligases that modify IMPDH2, the mechanism of IMPDH2 nuclear import, whether catalytic versus scaffolding functions are separable in the nuclear/chromatin compartment, and whether therapeutic modulation of filament assembly can rescue neurodevelopmental disease phenotypes.","evidence":"","pmids":[],"confidence":"Low","gaps":["E3 ligases for IMPDH2 K48 and K63 ubiquitination unidentified","Nuclear import signal and translocation mechanism unknown","No pharmacological strategy to selectively modulate filament assembly in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,4,7,18]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,9,14,16]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9,10,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[5]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,9,14,16]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,4,13,19]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,11]}],"complexes":["IMPDH2 cytoophidium filament","ANKRD9–IMPDH2 rod complex"],"partners":["ANKRD9","USP5","JOSD2","PARP1","PPIA","SRPK1","MYC","FANCI"],"other_free_text":[]},"mechanistic_narrative":"IMPDH2 is the rate-limiting enzyme of de novo guanine nucleotide biosynthesis, catalyzing the NAD+-dependent oxidation of IMP to XMP, and its activity is tuned by reversible polymerization into cytoophidium filaments that reduce sensitivity to allosteric GTP feedback inhibition [PMID:31999252, PMID:25601894]. Post-translational regulation is multilayered: CDK1-mediated phosphorylation at Ser122 inhibits catalytic activity (reversed by FGFR-activated PP2A) [PMID:39739531], USP5 removes K48-linked ubiquitin chains to stabilize the protein [PMID:40164869], JOSD2 cleaves K63-linked ubiquitin at K134 to suppress activity and NF-κB signaling [PMID:40177575], and ANKRD9 directs ubiquitin-dependent degradation under basal conditions while co-assembling into stabilizing filaments during nutrient limitation [PMID:31337707]. In the nucleus, IMPDH2 localizes to chromatin in a DNA-damage-dependent manner and modulates PARP1 activity through control of local NAD+ availability, linking guanine nucleotide metabolism to the DNA damage response [PMID:39532854]. Gain-of-function mutations in IMPDH2 cause dystonia and neurodevelopmental disorders by disrupting GTP-mediated allosteric inhibition and destabilizing Bateman domain dimerization required for filament assembly [PMID:37414152, PMID:41343675]."},"prefetch_data":{"uniprot":{"accession":"P12268","full_name":"Inosine-5'-monophosphate dehydrogenase 2","aliases":["Inosine-5'-monophosphate dehydrogenase type II","IMP dehydrogenase II","IMPDH-II"],"length_aa":514,"mass_kda":55.8,"function":"Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth (PubMed:7763314, PubMed:7903306). Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism (PubMed:14766016). It may also have a role in the development of malignancy and the growth progression of some tumors","subcellular_location":"Cytoplasm; Nucleus; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/P12268/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/IMPDH2","classification":"Common Essential","n_dependent_lines":620,"n_total_lines":1208,"dependency_fraction":0.5132450331125827},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PARP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IMPDH2","total_profiled":1310},"omim":[{"mim_id":"618605","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 9; ANKRD9","url":"https://www.omim.org/entry/618605"},{"mim_id":"617995","title":"IMPDH2 ENZYME ACTIVITY, VARIATION IN; IMPDH2V","url":"https://www.omim.org/entry/617995"},{"mim_id":"613381","title":"CYSTATHIONINE 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B","url":"https://pubmed.ncbi.nlm.nih.gov/41584327","citation_count":0,"is_preprint":false},{"pmid":"38328116","id":"PMC_38328116","title":"IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38328116","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.19.667179","title":"A Novel Allosteric Inhibitor Targeting IMPDH2 at Y233 Overcomes Resistance to Tyrosine Kinase Inhibitors in Lymphoma","date":"2025-08-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.19.667179","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.17.25335877","title":"AMPD2 deficiency implicates cytosolic purine metabolism in the pathogenesis of Leigh syndrome","date":"2025-09-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.17.25335877","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.16.617897","title":"Domain Specific AI Segmentation of IMPDH2 Rod/Ring Structures in Mouse Embryonic Stem Cells","date":"2024-10-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.16.617897","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.07.622457","title":"Epstein-Barr Virus Latent Membrane Protein 1 Subverts IMPDH pathways to drive B-cell oncometabolism","date":"2024-11-08","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.07.622457","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":39598,"output_tokens":6671,"usd":0.109429},"stage2":{"model":"claude-opus-4-6","input_tokens":10348,"output_tokens":4066,"usd":0.230085},"total_usd":0.339514,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structures of human IMPDH2 in active and inactive conformations revealed that filament assembly tunes allosteric regulation by making the enzyme less sensitive to GTP-mediated feedback inhibition, explaining why self-assembly occurs under conditions of high guanine nucleotide demand.\",\n      \"method\": \"Cryo-EM structural determination of multiple IMPDH2 conformations (active and inactive) with functional validation of allosteric regulation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures with multiple conformational states and functional mechanistic interpretation\",\n      \"pmids\": [\"31999252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IMPDH2 was identified as an intracellular target of the CyclophilinA (PPIA)–Sanglifehrin A (SFA) binary complex; the resulting ternary complex does not inhibit IMPDH2 enzymatic activity but instead interacts with the CBS (cystathionine-β-synthase) domain of IMPDH2 to modulate cell growth, demonstrating isoform selectivity for IMPDH2 over IMPDH1.\",\n      \"method\": \"Affinity pulldown, Co-IP, enzymatic activity assays, isoform selectivity assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal pulldown with enzymatic and cellular functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"28076787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANKRD9 facilitates ubiquitin-mediated degradation of IMPDH2 under basal conditions; upon nutrient limitation ANKRD9 co-assembles with IMPDH2 into rod-like filaments in which IMPDH2 is stable. The conserved Cys109–Cys110 motif in ANKRD9 is required for the vesicle-to-rod transition and for binding/regulation of IMPDH2. Guanosine acts as a metabolic switch reversing ANKRD9/IMPDH2 rod assembly.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of ANKRD9, fluorescence microscopy, IMPDH2 knockdown/overexpression, guanosine rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, mutagenesis, live imaging, KD/KO with rescue), single lab but strong mechanistic depth\",\n      \"pmids\": [\"31337707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Disease-associated point mutations in IMPDH2 linked to dystonia and neurodevelopmental disorders disrupt GTP-mediated allosteric regulation; cryo-EM structures of one mutant show a shift in conformational equilibrium toward a more active (GTP-inhibition-resistant) state.\",\n      \"method\": \"Cryo-EM structural analysis of IMPDH2 mutants, enzymatic activity assays measuring GTP inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures plus functional enzymatic assays with disease variants\",\n      \"pmids\": [\"37414152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IMPDH2 serine 122 is phosphorylated by CDK1, which attenuates IMPDH2 catalytic activity for IMP oxidation and represses allosteric modulation by purine nucleotides. FGFR signaling triggers dephosphorylation of Ser122 via PP2A (assembled through FGFR3-mediated phosphorylation of PPP2R1A-Tyr261, enabling PPP2CA–PPP2R1A–IMPDH2 interactions), thereby activating IMPDH2 to support guanine nucleotide synthesis, S-phase completion, and cell proliferation.\",\n      \"method\": \"In vitro kinase assay (CDK1), site-directed mutagenesis, phosphoproteomics, Co-IP, enzymatic activity assays, cell cycle analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro kinase assay plus mutagenesis, Co-IP of PP2A complex, multiple functional readouts\",\n      \"pmids\": [\"39739531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nuclear IMPDH2 interacts with PARP1 on chromatin and modulates PARP1 activity by controlling local NAD+ availability; IMPDH2 chromatin localization is DNA damage-dependent, and IMPDH2 repression leads to DNA damage accumulation. Restricting IMPDH2 exclusively to the nucleus depletes nuclear NAD+, triggering PARP1 cleavage and cell death.\",\n      \"method\": \"Chromatin fractionation, Co-IP on chromatin, NAD+ measurements, IMPDH2 knockdown with DNA damage readouts, nuclear-restricted IMPDH2 overexpression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (fractionation, Co-IP, NAD+ quantification, KD/forced localization) with strong functional link\",\n      \"pmids\": [\"39532854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP5 deubiquitinase binds IMPDH2 via its N-terminal cryptic ZnF-UBP and ZnF-UBP domains (interacting with IMPDH2 residues 251–514), removes Lys48-linked ubiquitin chains from IMPDH2, and thereby prevents its proteasomal degradation and stabilizes IMPDH2 protein levels to promote hepatocellular carcinoma proliferation and EMT.\",\n      \"method\": \"Co-IP domain mapping, deubiquitination assay (Lys48-linkage-specific), shRNA knockdown, xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — deubiquitination biochemical assay with linkage specificity, domain mapping, and in vivo rescue\",\n      \"pmids\": [\"40164869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JOSD2 deubiquitinase binds the C-terminus of IMPDH2 and cleaves K63-linked polyubiquitin chains at IMPDH2-K134, suppressing IMPDH2 enzymatic activity and preventing downstream NF-κB activation and inflammation in macrophages.\",\n      \"method\": \"Co-IP, site-specific deubiquitination assay (K63-linkage), JOSD2 knockout mice, myeloid-specific deletion with bone marrow transplantation\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — linkage-specific deubiquitination assay, K134 site identification, in vivo genetic models\",\n      \"pmids\": [\"40177575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Conditional deletion of Impdh2 in early neural crest cells (using Wnt1-Cre) in mice produces defects in multiple neural crest derivatives, including intestinal aganglionosis, craniofacial skeletal agenesis, and cardiac outflow tract malformations, demonstrating that IMPDH2-mediated guanine nucleotide synthesis is essential for neural crest cell proliferation and development.\",\n      \"method\": \"Conditional knockout mouse (Wnt1-Cre × Impdh2flox), Rosa26 reporter lineage tracing, histological analysis of neural crest derivatives\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with multiple specific phenotypic readouts in defined cell lineage\",\n      \"pmids\": [\"26546974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IMPDH2 is a major structural component (building block) of cytoplasmic rod/ring (RR) structures; microinjection of affinity-purified anti-IMPDH2 antibodies into live cells caused disassembly of RR structures within 10 minutes, demonstrating that IMPDH2 is essential for RR integrity and that mature RR are primarily stationary structures.\",\n      \"method\": \"Microinjection of anti-IMPDH2 antibodies into live cells, GFP-tagged IMPDH2 live imaging, fluorescence microscopy\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct live-cell antibody perturbation experiment with two independent methods (antibody injection + GFP-IMPDH2 imaging)\",\n      \"pmids\": [\"25601894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Assembly of IMPDH2-based rod/ring (RR) structures in cells is induced by inhibition of GTP biosynthesis (by ribavirin or mycophenolic acid) and is cell-type dependent; CTPS and IMPDH2 can form mixed or separate RR structures depending on cell type and the inhibitor used, indicating that IMPDH2 and CTPS independently organize into cytoophidia.\",\n      \"method\": \"Drug treatment (DON, ribavirin, MPA), immunofluorescence, transfection of NHA-tagged CTPS1 in HeLa and COS-7 cells\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, direct imaging with pharmacological manipulation but no biochemical reconstitution\",\n      \"pmids\": [\"26165495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SARS-CoV-2 Nsp14 protein physically interacts with IMPDH2, and this interaction is required for Nsp14-mediated NF-κB activation and pro-inflammatory cytokine (IL-6, IL-8) induction; IMPDH2 knockdown or pharmacological inhibition (ribavirin, mycophenolic acid) abolishes Nsp14-driven NF-κB activation and restricts SARS-CoV-2 replication.\",\n      \"method\": \"Co-IP confirmation of Nsp14–IMPDH2 interaction, siRNA knockdown, pharmacological inhibition, NF-κB reporter assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP confirmed interaction with functional KD and pharmacological validation, single lab\",\n      \"pmids\": [\"36177032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FANCI directly binds IMPDH2 (shown by Co-IP), decreases IMPDH2 degradation, and promotes MEK/ERK/MMP signaling activation; overexpression of IMPDH2 reverses the growth inhibitory effects of FANCI knockdown in lung adenocarcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence microscopy, Western blotting, FANCI knockdown with IMPDH2 rescue\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with epistasis rescue experiment\",\n      \"pmids\": [\"32021289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CircPFKP directly interacts with IMPDH2 and promotes guanine nucleotide biosynthesis; replenishment of the intracellular guanine nucleotide pool reverses the proliferation-inhibitory effects of circPFKP knockdown, placing IMPDH2 downstream of circPFKP in prostate cancer cell proliferation.\",\n      \"method\": \"RNA-protein interaction assays, circRNA knockdown, guanosine rescue experiments, cell cycle analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, direct RNA-protein interaction with metabolite rescue supporting pathway placement\",\n      \"pmids\": [\"34673127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IMPDH2 cytoophidium (filament) formation in neurodegeneration-resistant brain regions protects against GTP deprivation in AMPD2-deficient mice; IMPDH2 filaments are abundant in resistant regions but sparse in the vulnerable hippocampal dentate gyrus, and blocking IMPDH2 polymerization impairs GTP levels and growth of AMPD2-deficient neural progenitor cells.\",\n      \"method\": \"Mouse knockout models, immunofluorescence of IMPDH2 filaments, dominant-negative IMPDH2 variant to block polymerization, neural progenitor cell growth assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model with mechanistic IMPDH2 filament perturbation and cell growth readout\",\n      \"pmids\": [\"39075237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IMPDH2 filaments resist allosteric inhibition by GTP in regenerating Xenopus tropicalis tadpole tail tissue; IMPDH2 inhibition impairs tail regeneration and reduces cell proliferation, demonstrating that IMPDH2 filament assembly is a physiologically relevant regulatory mechanism in vertebrate tissue regeneration.\",\n      \"method\": \"Chemical inhibition of IMPDH2, IMPDH2-fluorescent fusion live imaging in regenerating tadpole tail, cell proliferation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vivo imaging of endogenous IMPDH2 filaments with functional inhibition in vertebrate regeneration context\",\n      \"pmids\": [\"39131357\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"An IMPDH2 neurodevelopmental disorder mutant (S160del) disrupts filament assembly by destabilizing dimerization of regulatory Bateman domains (shown by cryo-EM), alters purine pools in vivo in Xenopus tropicalis, and disrupts somite organization; GTP inhibition insensitivity of S160del is separable from Bateman domain dimerization, indicating that filament assembly and allosteric GTP regulation are mechanistically distinct.\",\n      \"method\": \"Cryo-EM structural analysis of S160del mutant, Xenopus tropicalis in vivo expression, metabolomics of purine pools, developmental phenotyping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure of disease mutant combined with in vivo metabolomics and developmental phenotypes in vertebrate model\",\n      \"pmids\": [\"41343675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A promoter SNP in IMPDH2 (c.-95T>G) disrupts a cyclic AMP response element (CRE) binding site and significantly decreases IMPDH2 transcriptional activity (~55–65% reduction) as measured by luciferase reporter assays in transfected HEK293 and Jurkat cells.\",\n      \"method\": \"Luciferase reporter gene assay, transient transfection in two cell lines\",\n      \"journal\": \"Genetic testing and molecular biomarkers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional reporter assay with two cell types, but single lab\",\n      \"pmids\": [\"19810816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"An IMPDH2 allozyme (Phe263) shows decreased enzymatic activity primarily due to accelerated protein degradation; these functional consequences are supported by the IMPDH2 X-ray crystal structure context.\",\n      \"method\": \"Enzyme activity assays, protein stability assays, resequencing of IMPDH2 in 288 individuals, X-ray crystal structure interpretation\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct enzymatic and protein stability assays on variant allozyme\",\n      \"pmids\": [\"20718729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Impdh2 deletion in myeloid lineage cells (Impdh2LysM-/- mice) impairs osteoclastogenesis by suppressing osteoclast marker gene expression and mitochondrial oxidative phosphorylation, and alleviates ovariectomy-induced bone loss in vivo. IMPDH inhibitor (MPA) treatment induces IMPDH2 cytoophidium (filament) formation coincident with osteoclast differentiation block.\",\n      \"method\": \"Conditional myeloid-specific Impdh2 knockout mouse, histomorphometry, qPCR, genome-wide transcriptomics, MPA pharmacological inhibition, OVX mouse model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with specific cellular and transcriptomic phenotypes, replicated with pharmacological inhibition\",\n      \"pmids\": [\"38959733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EBV induces IMPDH2 expression through EBNA2-dependent and MYC-dependent mechanisms (established using EBNA2 and LMP1 knockout viruses), leading to nucleolar hypertrophy and efficient B-cell growth transformation; IMPDH2 inhibition with MPA blocks this transformation.\",\n      \"method\": \"EBV knockout virus infections (EBNA2 KO, LMP1 KO), RNA-seq, MPA pharmacological inhibition, xenograft mouse model\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — viral genetic dissection with KO viruses, RNA-seq, and in vivo model\",\n      \"pmids\": [\"37409959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IMPDH2 interacts with c-Myc to protect it from ubiquitination; the natural compound vitexicarpin binds IMPDH2, disrupts the IMPDH2–c-Myc interaction, and promotes c-Myc ubiquitination leading to EMT inhibition in colorectal cancer.\",\n      \"method\": \"Co-IP, ubiquitination assay, CETSA, label-free quantitative proteomics, Biacore binding assay, molecular docking, IMPDH2 overexpression/knockdown rescue\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple orthogonal binding and functional methods but single lab\",\n      \"pmids\": [\"39008915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IMPDH2 is directly phosphorylated at tyrosine 233 (Y233) within its Bateman domain by ALK and SRC oncogenic kinases; Y233 phosphorylation is essential for IMPDH2 enzymatic activity. Phosphoinositide-3-phosphate (PI3P) selectively binds and inhibits IMPDH2 but not IMPDH1, representing an isoform-specific lipid-mediated regulatory mechanism.\",\n      \"method\": \"Peptide-based mutagenesis, in vitro kinase assays (ALK, SRC), enzymatic assays, PI3P binding assays, isoform selectivity comparison\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase and enzymatic assays with mutagenesis, but preprint only\",\n      \"pmids\": [\"bio_10.1101_2025.08.19.667179\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IMPDH2 interacts with SRPK1 in CD4+ T cells (confirmed by mass spectrometry, Co-IP, and confocal colocalization); IMPDH2 upregulates SRPK1 expression, which in turn activates the AKT/mTOR signaling pathway to promote CD4+ T cell proliferation and suppress apoptosis.\",\n      \"method\": \"Mass spectrometry interaction screen, Co-IP, confocal fluorescence colocalization, IMPDH2 knockdown/overexpression, Western blot of AKT/mTOR pathway\",\n      \"journal\": \"Clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — MS-confirmed interaction validated by Co-IP and colocalization, with functional pathway readout\",\n      \"pmids\": [\"41213488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"tRF-1432 (a 5'-tRNA^Val-CAC-derived fragment generated by angiogenin cleavage) directly interacts with RNA-binding protein RBMS1, attenuating RBMS1-mediated destabilization of IMPDH2 mRNA and thereby increasing IMPDH2 protein levels and GTP-dependent chemoresistance in breast cancer.\",\n      \"method\": \"High-throughput sequencing, RNA-protein interaction assays, RBMS1 knockdown/rescue, IMPDH2 mRNA stability assays, syngeneic tumor models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct RNA-protein interaction with mRNA stability mechanistic follow-up and in vivo model\",\n      \"pmids\": [\"41791844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IMPDH2 forms localized spots at branching sites and distal ends of astrocyte stem processes in adult mouse hippocampus, suggesting a role in site-specific GTP synthesis and local small GTPase regulation at specialized nodes in astrocyte branches.\",\n      \"method\": \"Immunofluorescence of endogenous IMPDH2 in adult mouse hippocampus and primary astrocyte cultures, quantitative distribution analysis\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — localization data without direct functional consequence demonstrated\",\n      \"pmids\": [\"38009721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IMPDH2 cytoophidium forms in vivo in growing mouse oocytes and in granulosa cells following LH surge; MPA-induced IMPDH2 cytoophidium formation in cumulus cells coincides with meiosis resumption in oocytes mediated through the mTOR pathway, and this effect is reversed by guanosine supplementation, linking IMPDH2 filament formation to oocyte meiotic competence.\",\n      \"method\": \"In vivo immunofluorescence in mouse ovary, MPA pharmacological inhibition, mTOR pathway inhibitor, guanosine rescue, confocal microscopy\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — in vivo localization with pharmacological perturbation and metabolite rescue linking IMPDH2 filaments to meiotic signaling\",\n      \"pmids\": [\"34124077\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IMPDH2 is the rate-limiting enzyme catalyzing the first committed step of de novo guanine nucleotide biosynthesis (IMP → XMP), whose activity is allosterically inhibited by GTP; it reversibly polymerizes into filaments that reduce sensitivity to GTP-mediated feedback inhibition, and its activity is regulated post-translationally by CDK1-mediated phosphorylation at Ser122 (inhibitory, reversed by FGFR-activated PP2A), by ALK/SRC-mediated phosphorylation at Tyr233 (activating), by USP5-mediated deubiquitination (stabilizing) and JOSD2-mediated K63-deubiquitination (inhibitory), and by ANKRD9-mediated ubiquitination-dependent degradation; in the nucleus IMPDH2 modulates PARP1 activity via NAD+ availability to fine-tune the DNA damage response, and gain-of-function disease mutations associated with dystonia and neurodevelopmental disorders disrupt GTP allostery by shifting the conformational equilibrium toward an active state and destabilizing Bateman domain dimerization required for filament assembly.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IMPDH2 is the rate-limiting enzyme of de novo guanine nucleotide biosynthesis, catalyzing the NAD+-dependent oxidation of IMP to XMP, and its activity is tuned by reversible polymerization into cytoophidium filaments that reduce sensitivity to allosteric GTP feedback inhibition [PMID:31999252, PMID:25601894]. Post-translational regulation is multilayered: CDK1-mediated phosphorylation at Ser122 inhibits catalytic activity (reversed by FGFR-activated PP2A) [PMID:39739531], USP5 removes K48-linked ubiquitin chains to stabilize the protein [PMID:40164869], JOSD2 cleaves K63-linked ubiquitin at K134 to suppress activity and NF-κB signaling [PMID:40177575], and ANKRD9 directs ubiquitin-dependent degradation under basal conditions while co-assembling into stabilizing filaments during nutrient limitation [PMID:31337707]. In the nucleus, IMPDH2 localizes to chromatin in a DNA-damage-dependent manner and modulates PARP1 activity through control of local NAD+ availability, linking guanine nucleotide metabolism to the DNA damage response [PMID:39532854]. Gain-of-function mutations in IMPDH2 cause dystonia and neurodevelopmental disorders by disrupting GTP-mediated allosteric inhibition and destabilizing Bateman domain dimerization required for filament assembly [PMID:37414152, PMID:41343675].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing that IMPDH2 transcription is regulated by a cAMP response element answered how signaling pathways control enzyme abundance at the promoter level.\",\n      \"evidence\": \"Luciferase reporter assays with a promoter SNP (c.−95T>G) disrupting a CRE site in HEK293 and Jurkat cells\",\n      \"pmids\": [\"19810816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous transcription factor binding not confirmed by ChIP\", \"In vivo relevance of this SNP not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that a naturally occurring IMPDH2 allozyme (Phe263) loses activity primarily through accelerated degradation revealed that protein stability, not just catalytic efficiency, governs IMPDH2 function.\",\n      \"evidence\": \"Enzymatic activity and protein stability assays on variant allozyme, interpreted against X-ray crystal structure\",\n      \"pmids\": [\"20718729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation pathway (ubiquitin vs. autophagy) not identified\", \"Clinical pharmacogenomic impact not quantified in vivo\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing IMPDH2 as the essential structural building block of cytoplasmic rod/ring (cytoophidium) structures, and showing that these filaments form in response to GTP biosynthesis inhibition, defined a novel metabolic ultrastructure and its assembly triggers.\",\n      \"evidence\": \"Microinjection of anti-IMPDH2 antibodies causing rapid RR disassembly; pharmacological induction by ribavirin/MPA with immunofluorescence in multiple cell types\",\n      \"pmids\": [\"25601894\", \"26165495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution filament architecture not yet determined at this time\", \"Functional consequence of filament assembly on enzyme kinetics not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Conditional deletion of Impdh2 in neural crest cells demonstrated that IMPDH2-dependent guanine nucleotide synthesis is essential for neural crest proliferation and organogenesis, establishing a non-redundant developmental role.\",\n      \"evidence\": \"Wnt1-Cre conditional knockout mouse with Rosa26 lineage tracing showing aganglionosis, craniofacial agenesis, and cardiac outflow tract defects\",\n      \"pmids\": [\"26546974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IMPDH1 can partially compensate in other lineages not tested\", \"Mechanism downstream of GTP depletion (proliferation vs. differentiation defect) not dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of IMPDH2 as the isoform-selective target of the CyclophilinA–Sanglifehrin A complex revealed a non-catalytic regulatory interface on the CBS/Bateman domain that modulates cell growth.\",\n      \"evidence\": \"Affinity pulldown and Co-IP with enzymatic activity assays showing no catalytic inhibition; isoform selectivity over IMPDH1\",\n      \"pmids\": [\"28076787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PPIA–SFA–IMPDH2 ternary complex not resolved\", \"Growth-modulating mechanism downstream of CBS domain engagement unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that ANKRD9 acts as a metabolic switch — promoting IMPDH2 ubiquitin-dependent degradation basally but co-assembling into stabilizing filaments under nutrient limitation — revealed how IMPDH2 protein levels are coupled to metabolic state.\",\n      \"evidence\": \"Co-IP, mutagenesis of ANKRD9 Cys109–Cys110, fluorescence microscopy of rod assembly, guanosine rescue experiments\",\n      \"pmids\": [\"31337707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase that ubiquitinates IMPDH2 via ANKRD9 not identified\", \"Stoichiometry of ANKRD9 within filaments unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cryo-EM structures of IMPDH2 filaments in active and inactive conformations answered the long-standing question of how polymerization is functionally meaningful: filament assembly desensitizes the enzyme to GTP feedback inhibition, explaining filament formation under high guanine nucleotide demand.\",\n      \"evidence\": \"Cryo-EM of multiple conformational states with allosteric regulation functional assays\",\n      \"pmids\": [\"31999252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo validation that filament-mediated desensitization drives proliferative advantage not yet shown\", \"Dynamics of filament assembly/disassembly in real time not captured\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Observation of IMPDH2 cytoophidium formation in mouse oocytes and granulosa cells in vivo, with pharmacological evidence linking filaments to mTOR-dependent meiosis resumption, extended the physiological relevance of IMPDH2 polymerization to reproductive biology.\",\n      \"evidence\": \"In vivo immunofluorescence in mouse ovary, MPA-induced filament formation with mTOR inhibitor and guanosine rescue\",\n      \"pmids\": [\"34124077\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct genetic test (IMPDH2 polymerization-deficient mutant) in oocytes not performed\", \"Whether filaments alter local GTP pools in granulosa cells not measured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that SARS-CoV-2 Nsp14 physically engages IMPDH2 to activate NF-κB signaling uncovered a viral hijacking mechanism that links purine metabolism to innate immune activation.\",\n      \"evidence\": \"Co-IP of Nsp14–IMPDH2, siRNA knockdown and pharmacological inhibition abolishing NF-κB reporter activation\",\n      \"pmids\": [\"36177032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IMPDH2 enzymatic activity or a scaffolding role is required for Nsp14-mediated NF-κB not distinguished\", \"Interaction validated in single lab only\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cryo-EM structures of disease-linked IMPDH2 mutants established the molecular basis of dystonia and neurodevelopmental disorders: mutations shift the conformational equilibrium toward an active, GTP-inhibition-resistant state.\",\n      \"evidence\": \"Cryo-EM of mutant IMPDH2, enzymatic assays measuring reduced GTP inhibition\",\n      \"pmids\": [\"37414152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neuronal cell-type-specific consequences of gain-of-function not modeled\", \"Whether pharmacological IMPDH2 inhibition can rescue disease phenotype untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that CDK1 phosphorylates IMPDH2 at Ser122 to inhibit activity, and that FGFR signaling reverses this through PP2A-mediated dephosphorylation, established a cell-cycle-coupled regulatory circuit linking mitogenic signaling to guanine nucleotide supply during S-phase.\",\n      \"evidence\": \"In vitro CDK1 kinase assay, phosphosite mutagenesis, Co-IP of PP2A complex, cell cycle analysis\",\n      \"pmids\": [\"39739531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Ser122 phosphorylation affects filament assembly not tested\", \"In vivo validation in animal models lacking\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that nuclear IMPDH2 interacts with PARP1 on chromatin and controls local NAD+ availability revealed an unexpected non-canonical role: IMPDH2 couples purine metabolism to the DNA damage response by modulating PARP1 activity.\",\n      \"evidence\": \"Chromatin fractionation, Co-IP on chromatin, NAD+ measurements, nuclear-restricted IMPDH2 overexpression causing PARP1 cleavage and cell death\",\n      \"pmids\": [\"39532854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of IMPDH2 nuclear import not identified\", \"Whether IMPDH2 catalytic activity or scaffolding is required on chromatin not fully separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that IMPDH2 filaments accumulate in neurodegeneration-resistant brain regions of AMPD2-deficient mice, and that blocking polymerization impairs neural progenitor GTP levels, established filament formation as a neuroprotective mechanism against purine imbalance.\",\n      \"evidence\": \"Mouse knockout model of AMPD2, immunofluorescence of IMPDH2 filaments, dominant-negative polymerization mutant in neural progenitors\",\n      \"pmids\": [\"39075237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal relationship between filament abundance and regional vulnerability not genetically proven\", \"Whether therapeutic promotion of filament assembly is feasible not explored\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Myeloid-specific Impdh2 deletion suppressed osteoclastogenesis and protected against ovariectomy-induced bone loss, revealing IMPDH2 as a metabolic gatekeeper of osteoclast differentiation through control of oxidative phosphorylation.\",\n      \"evidence\": \"LysM-Cre conditional knockout, histomorphometry, transcriptomics, MPA pharmacological inhibition in OVX mouse model\",\n      \"pmids\": [\"38009733\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GTP depletion or secondary metabolic effects drive osteoclast block not dissected\", \"Contribution of IMPDH1 in myeloid cells not assessed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of USP5 as a K48-linkage-specific deubiquitinase stabilizing IMPDH2, and JOSD2 as a K63-linkage-specific deubiquitinase suppressing IMPDH2 activity at K134, revealed that distinct ubiquitin chain types exert opposing regulatory outcomes — stability versus activity modulation.\",\n      \"evidence\": \"USP5: domain mapping, K48-specific DUB assay, xenograft rescue; JOSD2: K63-specific DUB assay at K134, JOSD2 KO mice with macrophage phenotypes\",\n      \"pmids\": [\"40164869\", \"40177575\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligases conjugating K48 and K63 chains on IMPDH2 not identified\", \"Whether ubiquitin editing occurs on filament-assembled versus free IMPDH2 unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-EM of the S160del disease mutant demonstrated that filament assembly and allosteric GTP regulation are mechanistically separable: S160del destabilizes Bateman domain dimerization (disrupting filaments) while independently retaining GTP insensitivity, refining the structure-function model of IMPDH2 regulation.\",\n      \"evidence\": \"Cryo-EM of S160del, Xenopus in vivo expression with metabolomics and somite phenotyping\",\n      \"pmids\": [\"41343675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether filament disruption alone is sufficient for disease pathogenesis not tested\", \"Neuronal-specific consequences of Bateman domain destabilization not modeled in mammalian systems\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of E3 ubiquitin ligases that modify IMPDH2, the mechanism of IMPDH2 nuclear import, whether catalytic versus scaffolding functions are separable in the nuclear/chromatin compartment, and whether therapeutic modulation of filament assembly can rescue neurodevelopmental disease phenotypes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"E3 ligases for IMPDH2 K48 and K63 ubiquitination unidentified\", \"Nuclear import signal and translocation mechanism unknown\", \"No pharmacological strategy to selectively modulate filament assembly in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 4, 7, 18]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 9, 14, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9, 10, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 9, 14, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 4, 13, 19]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 11]}\n    ],\n    \"complexes\": [\n      \"IMPDH2 cytoophidium filament\",\n      \"ANKRD9–IMPDH2 rod complex\"\n    ],\n    \"partners\": [\n      \"ANKRD9\",\n      \"USP5\",\n      \"JOSD2\",\n      \"PARP1\",\n      \"PPIA\",\n      \"SRPK1\",\n      \"MYC\",\n      \"FANCI\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}